Aliquots - research highlights from VUMC laboratories

With a 5-year survival of less than 5 percent, pancreatic cancer is one of the most lethal forms of cancer, and conventional chemotherapy offers only a modest survival benefit. Drugs that inhibit the proto-oncogene Src have shown promise in animal models of pancreatic cancer, but their molecular actions are not well understood.

In the August issue of Molecular Cancer Therapeutics, Nipun Merchant, M.D., Nagaraj Nagathihalli, Ph.D., and colleagues report the molecular effects of the Src inhibitor dasatinib – a drug approved to treat some leukemias – in human pancreatic cancer cell lines.

They found that dasatinib stimulates cell death (apoptosis) and inhibits cell proliferation, migration and invasion through multiple signaling pathways in cultured cells, which correlated to reduced tumor growth in mice with implanted pancreatic tumors. The study also demonstrated for the first time that Src localization within the cell impacts patient survival, with increased membrane expression associated with decreased survival. The findings establish a rationale for Src inhibition in treating pancreatic cancer and identify possible biomarkers for resistance to dasatinib treatment.

— Melissa Marino

Capping off HIV infection

HIV can cause disease in humans and not monkeys because monkey cells restrict the virus’ entry or replication. TRIM proteins found in host cells block an early step in HIV infection, which may involve altering the viral capsid, the cone-shaped shell that encloses its genetic material.

graphic by Dominic Doyle

Lesa Black, Ph.D., and Christopher Aiken, Ph.D., examined the structural effects of TRIM5 proteins on the assembly of CA-NC complexes that make up the viral capsid. They show that incubating these complexes with TRIM5α (the factor from rhesus monkey that restricts HIV) and TRIMCyp (from owl monkeys) disrupted their normal cylindrical structure. But incubating the complexes with human TRIM5α, which only weakly restricts HIV, had little effect.

The results, reported in the July Journal of Virology, suggest that TRIM5α disturbs the structure of the viral capsid, leading to abnormal “uncoating” of the genetic material. Understanding and exploiting this restriction mechanism may aid the development of novel antiviral therapies.

— Melissa Marino

Cellular ‘power’ protects neurons

Defects in energy production by cellular “power plants” – mitochondria – have been linked to neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s and Huntington’s diseases.

iStockphoto.com

To explore the molecular events that connect mitochondrial dysfunction to cell death, David Miller, Ph.D., and graduate students Laurie Earls and Mallory Hacker generated a model in the nematode worm, Caenorhabditis elegans. They knocked down the genes required to synthesize Coenzyme Q, a key factor for mitochondrial energy production. The researchers report in the Aug. 10 Proceedings of the National Academy of Sciences that reduced levels of Coenzyme Q resulted in progressive loss of motor coordination and selective degeneration of neurons that use the neurotransmitter GABA. They found that the neuronal degeneration depended on calcium and required a gene that mediates apoptosis, a specific type of cell death.

The findings point to a role for Coenzyme Q in neuron survival and suggest that the C. elegans model may be useful for understanding how defects in mitochondrial function trigger neurodegeneration.

— Leigh MacMillan

New approach to stifle stomach bug

The bacterium Helicobacter pylori infects about half of the world’s population. It induces immune responses, but these responses do not eliminate the bug. H. pylori persists in the human stomach for decades, leading to chronic inflammation, peptic ulcers, lymphoma and stomach cancer.

Keith Wilson, M.D., and colleagues are exploring the failure of the immune response against H. pylori. They previously showed that H. pylori induces the production of the microbe-killing chemical nitric oxide by macrophages, but not enough to eliminate the bug. They now report in the journal Gastroenterology that chemicals called polyamines – also produced by macrophages – limit the production (and therefore killing power) of nitric oxide. Treatment of H. pylori-infected mice with an inhibitor of polyamine production increased nitric oxide synthesis and reduced both H. pylori colonization levels and the severity of stomach inflammation.

The findings suggest that modulation of polyamine generation in the stomach may be a novel approach for enhancing immunity to H. pylori.

— Leigh MacMillan

We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.